Diastereoisomeric propane derivatives and process for their manufacture



Patented Dec. 22, 1953 2,663,727 OFFICE ,DIASTEREQISOMERIC PROPANEv DERIVA- TIYESi AND PROCESS FOR'THEIR .MANU- "FACTURE Paul .Gailliot}? JE'aris;- and Jean Robert, -Maisns Izaffi-tte,-.- France; assignors, by mesne "assign-V .ments, .to Parke, Davisl.r& Company, Detroit,

:Mich,, acorporation of Michigan ;-iNo.-l)rawing."Application February 23, 1951, IjSeriallNo. 212,491

.i' laimsnri rity, appli ation-France QOctober 28,1950

Rebstocket al; (J. A. C. 8., vol. '11, pp." 2458- 2473) in connection with the iastereoisomeric 'amido diol, Z-dichloracetamido-l-p-nitrophenylpropane 1:3-diol, an optically active isomer of which is known by the common name -Chloramphenico'l, structural isomeric forms areherein=referred to as *erythro and threo-respectiv-ely-while the racemic mixture and individual optical isomers corresponding to each of these structural isomeric formsare designated DL, L and D respectively. "Cohfigurationalrepresentation of'the isomers as-D and L refers not to actual sign of rotation but to configuration about the alpha carbon; atom. ;'Thus' *the D threo compounds hereinafterreferred to. have 'the sarne configuration with respect :to the alpha carbon 01 noigtn c in-cm o con in'which vR. represents an unsubstituted or substituted aliphatic or :aromatic radical or an alkoxy group. These compounds are disclosed and claimed in the co-pending application of Jacob and Robert, Serial No. 212,489, filed on even date herewith. In one embodiment under the above formula, the radical R rep-resents a lower alkyl group or a phenyl group. In another embodiment, the radical OCOR is derived from a dibasic carboxylic acid, such as succinic acid, and, therefore, R then has the form --R'COOR" where R represents an alkylene or arylene group and R" represents hydrogen or an alkyl group.

According to this invention, these new compounds are obtained from the corresponding threo esters represented by the general formula:

OH Nn-oo-oacu n (where R is as hereinbefore defined) by treatment with thionyl chloride under anhydrous conditions.

. Theesters pffFormuiaII employed. as start- ..ing materials may .beobtained, for example, by

.the action of carboxylic acid chlorides. or anhydridesor in certain cases, of chloro carbonic esters, in the presence, of a tertiary base, upon threo 2 dichloroacetamido-i-p-nitrophenylpropane 1,: 3-diols.

It will be appreciated that since the starting material used in the production of the compounds ofthe present invention can -.exist in optically isomeric forms, it is necessary, if a particularop- .tical isomer ofthe .final product is to he obtained either to use the starting material in the form of the corresponding isomer or to resolve the racemate produced in the processes hereinbefore described.

The DL and D threo esters of 2-dich1oracetamido-l-p-nitrophenyl-l chloro '3 hydroxypropane of the present invention are important intermediates forthe preparation of chloramphenicoland the corresponding DL form thereof andlalso forthe preparation of the useful oxazolines D and 1 DL-threo xi-dichloromethyl-fi -pnitrophenyl-4-l'iydroxymethyl-A oXazolines-,as disclosed and claimed in the co-pending appli cation of Jacob and Robert, Serial No. 212490, filed on even date herewith.

The following, non-limitative examples illustrate the invention:

v.Ea'a rrnplel 7 To a solution of 12 -g...of racemic'threoZ-dh 'chloracetam'ido-l p nitrophenyl 3 acetoxypropane l-ol-of M5 P. 132-133" C. in 20 c. c.1of anhydrous dioxane and 2.6 g. of anhydrous pyridine, are laddedpwith agitation and cooling,

' the residue from 45 c. c. of benzene, 10.7 g. of

racemic threo 2 dichloracetamido-l-p-nitrophenyl-1-chloro-B-acetoXy-prOpane, M. P. 118- 119 C., are obtained. A second crystallisation raises the melting point to 120-121 C.

Example II To a solution of 14.7 g. of D-threo Z-dichloracetamido-l-p-nitrophenyl-B acetoxy propane 1-01 in 30 c. c. of anhydrous dioxane and 3.48 g. of anhydrous pyridine, are added, with agitation and cooling, 5.25 g. of pure thionyl chloride (distilled over linseed oil). The mixture is then heated in a bath at 90100 C. for 4-0 minutes and the dioxane distilled off in vacuo in the cold. The oily residue is redissolved in 80 c. c. of chloroform, and the chloroform solution is washed with water, dried over sodium sulphate and decolourised with charcoal. The chloroform is driven off in vacuo in the cold. 16.5 g. of D-threo 2-didichloracetamido-lp-nitrophenyl-1 chloro 3- acetoxypropane are obtained which, after recrystallisation from ethyl alcohol, melt at 101- 102C., and has a rotatory power of (a) =-8 (c=6.4% in ethyl acetate).

Example III To a solution of 4 g. of D-threo Z-dichloracetamido-l-p-nitrophenyl-3 benzoyloxy propane l-ol of M. P. 199-200 C. and (a) =29.3 (c=4% in acetone) in 50 c. c. of anhydrous dioxane and 0.82 g. of anhydrous pyridine, are added, with agitation and cooling, 1.22 g. of pure thionyl chloride (distilled over linseed oil). The product is then heated to 85-90" C. for 50 minutes, and the dioxane is then distilled off in vacuo in the cold. The residue is taken up in 50 c. c. of chloroform and the solution washed with water, dried over sodium sulphate and decolourised with charcoal. The chloroform is removed in vacuo. 4 g. of D-threo 2-dichloracetamido-l-p-nitrophenyl-l-chloro-3-benzoyloxypropane are obtained; M. P. '7109 C.

After recrystallisation from ethyl alcohol, the product melts at 1-09-110 C., (a) -3 (c=4% in ethyl acetate).

We claim:

1. Process comprising heating a threo compound of formula noOtn-oncmocoa with thionyl chloride under anhydrous conditions and in the presence of a, solvent at a temperature of 80-100 0., thereby producing a threo compound of formula NHCO-CHCI:

wherein R is a radical of the class consisting of lower alkyl and phenyl groups; 4

2. Process according to claim 1 wherein an excess of thionyl chloride is employed, the reagents are refluxed together in a solvent medium until the reaction is substantially complete and the excess thionyl chloride and solvent removed by distillation under reduced pressure.

3. Process which comprises heating DL-threo- 1 p nitrophenyl 2 dichloracetamido 3 acetoxypropane 1 01 with thionyl chloride under anhydrous conditions and in the presence of a solvent at a temperature of -100 0., thereby producing DL-threo-l-p-nitrophenyl-lchloro-2-dichloracetamido 3 acetoxypropane.

4. Process which comprises heating D-threo- 1 p nitrophenyl 2 dichloracetamido 3 acetoxypropane-l-ol with thionyl chloride under anhydrous conditions and in the presence of a solvent at a temperature of 80-100 C., thereby producing D-threo-l-p-nitrophenyl-l-chloro-2- dichloracetamido-3-acetoxypropane.

5. Process comprising refluxing at a temperature of 80-100" C. DL-threo-1-p-nitrophenyl-2- dich1oracetamido-3-acetoxypropane-1-ol with an excess of thionyl chloride in an anhydrous solvent medium until the reaction is substantially complete and the excess thionyl chlorid and solvent removed by distillation under reduced pressure thereby obtaining DL-threo-l-p-nitrophenyl-1- ch1oro-2-dich1oracetamido-3-acetoxypropane.

6. Process comprising refluxing at a temperature of 80-100 C. D-threo-l-p-nitrophenyl-2- dichloracetamido-3-acetoxypropane-l-ol with an excess of thionyl chloride in an anhydrous solvent medium until the reaction is substantially complete and the excess thionyl chloride and solvent removed by distillation under reduced pressure thereby obtaining D-threo-l-p-nitrophenyl- 1 chloro-2-dichloracetamido-3-acetoxypropane.

'7. Process comprising refluxing at a temperature of 80-100 C. D-threo-l-p-nitrophenyl-2- dichloracetamido-3-benzoyloxypropane-l-ol with an excess of thionyl chloride in an anhydrous solvent medium until the reaction is substantially complete and the excess thionyl chloride and solvent removed by distillation under reduced pressure thereby obtaining D-threo-l-p-nitrophenyl- 1 chloro-2-dichloracetamido-3-benzoyloxy propane.

PAUL GAILLOT. JEAN ROBERT.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,513,346 Moersch et a1 July 4, 1950 2,562,114 Moersch et al. July 24, 1951 2,587,641 Moersch et a1 May 4, 1952 

1. PROCESS COMPRISING HEATING A THREO COMPOUND OF FORMULA WITH THIONYL CHLORIDE UNDER ANHYDROUS CONDITIONS AND IN THE PRESENCE OF A SOLVENT AT A TEMPERATURE OF 80-100* C., THEREBY PRODUCING A THREO COMPOUND OF FORMULA WHEREIN R IS A RADICAL OF THE CLASS CONSISTING OF LOWER ALKYL AND PHENYL GROUPS. 